Methylnicotinamide derivatives and formulations for treatment of lipoprotein abnormalities

Abstract

The present invention is directed to nicotinamide derivatives, and their use in treating lipoprotein abnormalities, alone or in combination with a statin.

1 . A pharmaceutical composition comprising a statin and a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 R represents the group NR 2 R 3  or the group OR 4 ;  
 R 1  represents methyl;  
 R 2  and R 4  each independently represent hydrogen or C 1-4 alkyl;  
 R 3  represents hydrogen, C 1-4 alkyl or CH 2 OH; and  
 X −  is a physiologically suitable counter-anion.  
 
   
   
       2 . The pharmaceutical composition as claimed in  claim 1  in which R represents the group NR 2 R 3 .  
   
   
       3 . The pharmaceutical composition of  claim 1  in which R 2  represents methyl or hydrogen.  
   
   
       4 - 6 . (canceled)  
   
   
       7 . The pharmaceutical composition of  claim 1  wherein the compound of Formula I is selected from a 1-methylnicotinamide salt or a 1-methyl-N′-hydroxymethylnicotinamide salt.  
   
   
       8 - 9 . (canceled)  
   
   
       10 . The pharmaceutical composition of  claim 1  wherein the salt is a chloride, benzoate, salicylate, acetate, citrate or lactate.  
   
   
       11 . The pharmaceutical composition of  claim 1  wherein the compound of Formula I is selected from 1-methylnicotinamide chloride, 1-methylnicotinamide citrate, 1-methylnicotinamide lactate, 1-methyl-N′-hydroxymethylnicotinamide chloride 1-methylnicotinic acid chloride, 1-methylnicotinic acid ethyl ester chloride or 1-methylnicotinic acid propyl ester chloride.  
   
   
       12 . The pharmaceutical composition of  claim 1 , wherein the statin is mevastatin, lovastatin, simvastatin, pravastatin, fluvastatin, pitavastatin, atorvastatin, cerivastatin, rosuvastatin, pentostatin or nystatin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, prodrug, or pharmacologically active metabolite thereof.  
   
   
       13 . A method of treating a lipoprotein abnormality in a subject in need thereof by administering to the subject a pharmaceutical composition comprising a statin and a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 R represents the group NR 2 R 3  or the group OR 4 ;  
 R 1  represents methyl;  
 R 2  and R 4  each independently represent hydrogen or C 1-4 alkyl;  
 R 3  represents hydrogen, C 1-4 alkyl or CH 2 OH; and  
 X −  is a physiologically suitable counter-anion.  
 
   
   
       14 . The pharmaceutical composition of  claim 13  in which R represents the group NR 2 R 3 .  
   
   
       15 . The pharmaceutical composition of  claim 13  in which R 2  represents methyl or hydrogen.  
   
   
       16 - 18 . (canceled)  
   
   
       19 . The pharmaceutical composition of  claim 13  wherein the compound of Formula I is selected from a 1-methylnicotinamide salt or a 1-methyl-N′-hydroxymethylnicotinamide salt.  
   
   
       20 - 21 . (canceled)  
   
   
       22 . The pharmaceutical composition of  claim 13  wherein the salt is a chloride, benzoate, salicylate, acetate, citrate or lactate.  
   
   
       23 . The pharmaceutical composition of  claim 13  wherein the compound of Formula I is selected from 1-methylnicotinamide chloride, 1-methylnicotinamide citrate, 1-methylnicotinamide lactate, 1-methyl-N′-hydroxymethylnicotinamide chloride 1-methylnicotinic acid chloride, 1-methylnicotinic acid ethyl ester chloride or 1-methylnicotinic acid propyl ester chloride.  
   
   
       24 . The pharmaceutical composition of  claim 13 , wherein the statin is mevastatin, lovastatin, simvastatin, pravastatin, fluvastatin, pitavastatin, atorvastatin, cerivastatin, rosuvastatin, pentostatin or nystatin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, prodrug, or pharmacologically active metabolite thereof.  
   
   
       25 . The method of  claim 13 , wherein the lipoprotein abnormality is a disease or disorder associated with the development and progress of atherosclerosis, hyperlipidaemias, angina pectoris or cardiac risk.  
   
   
       26 . The method of  claim 25 , wherein the disease or disorder associated with the development and progress of atherosclerosis is hypertension, dyslipidaemias, diabetes or obesity.  
   
   
       27 . The method of  claim 26 , wherein said treatment of atherosclerosis slows the progression of atherosclerotic plaques.  
   
   
       28 . The method of  claim 27 , wherein said progression of atherosclerotic plaques is slowed in coronary arteries.  
   
   
       29 . The method of  claim 27 , wherein said progression of atherosclerotic plaques is slowed in carotid arteries.  
   
   
       30 . The method of  claim 27 , wherein said progression of atherosclerotic plaques is slowed in the peripheral arterial system.  
   
   
       31 . The method of  claim 27 , wherein said treatment of atherosclerosis causes the regression of atherosclerotic plaques.  
   
   
       32 . The method of  claim 27 , wherein said regression of atherosclerotic plaques occurs in coronary arteries.  
   
   
       33 . The method of  claim 27 , wherein the lipoprotein abnormality is associated with hypertension, cerebral vasospasm, coronary vasospasm, bronchial asthma, preterm labor, erectile dysfunction, glaucoma, vascular smooth muscle cell proliferation, myocardial hypertrophy, malignoma, ischemia-induced injury, reperfusion-induced injury, endothelial dysfunction, Crohn's Disease and colitis, neurite outgrowth, Raynaud's Disease, angina, Alzheimer's disease or benign prostatic hyperplasia.  
   
   
       34 . The method of  claim 13 , wherein the lipoprotein abnormality is associated with erectile dysfunction, reperfusion, ischemia, or vasospasm.  
   
   
       35 . The method of  claim 13 , wherein the lipoprotein abnormality is associated with dementia or cancer.  
   
   
       36 . The method of  claim 35 , wherein the cancer is selected from the group consisting of prostate, skin, lung, colon, bladder, uterus and kidney cancer.  
   
   
       37 . The method of  claim 13 , wherein the lipoprotein abnormality is associated with cardiovascular disease, peripheral vascular disease, dyslipidemia, dyslipoproteinemia, restenosis, a disorder of glucose metabolism, Alzheimer's Disease, Syndrome X, a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, renal disease, inflammation, inflammatory muscle diseases, such as polymylagia rheumatica, polymyositis, fibrositis, gastrointestinal disease, irritable bowel syndrome, inflammatory bowel disease, inflammatory disorders, impotence, arthritis, osteoporosis, soft tissue rheumatism, autoimmune disease, scleroderma, ankylosing spondylitis, gout, pseudogout, non-insulin dependent diabetes mellitus, septic shock, polycystic ovarian disease, hyperlipidemias, lipoprotein lipase deficiencies, lipoprotein abnormalities associated with diabetes, lipoprotein abnormalities associated with obesity, and lipoprotein abnormalities associated with Alzheimer's Disease.  
   
   
       38 - 50 . (canceled)  
   
   
       51 . A method of treating atherosclerosis in a subject in need thereof by administering to the subject a pharmaceutical composition comprising a statin and a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 R represents the group NR 2 R 3  or the group OR 4 ;  
 R 1  represents methyl;  
 R 2  and R 4  each independently represent hydrogen or C 1-4 alkyl;  
 R 3  represents hydrogen, C 1-4 alkyl or CH 2 OH; and  
 X −  is a physiologically suitable counter-anion.  
 
   
   
       52 . A method of lowering LDL-cholesterol levels in a subject in need thereof by administering to the subject a pharmaceutical composition comprising a statin and a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 R represents the group NR 2 R 3  or the group OR 4 ;  
 R 1  represents methyl;  
 R 2  and R 4  each independently represent hydrogen or C 1-4 alkyl;  
 R 3  represents hydrogen, C 1-4 alkyl or CH 2 OH; and  
 X −  is a physiologically suitable counter-anion.  
 
   
   
       53 . A method of raising HDL-cholesterol levels in a subject in need thereof by administering to the subject a pharmaceutical composition comprising a statin and a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     wherein 
 R represents the group NR 2 R 3  or the group OR 4 ;  
 R 1  represents methyl;  
 R 2  and R 4  each independently represent hydrogen or C 1-4 alkyl;  
 R 3  represents hydrogen, C 1-4 alkyl or CH 2 OH; and  
 X −  is a physiologically suitable counter-anion.  
 
   
   
       54 . The method of claims  51 ,  52  or  53 , wherein the statin is mevastatin, lovastatin, simvastatin, pravastatin, fluvastatin, pitavastatin, atorvastatin, cerivastatin, rosuvastatin, pentostatin, or nystatin, or a pharmaceutically acceptable salt, solvate, clathrate, polymorph, prodrug, or pharmacologically active metabolite thereof.  
   
   
       55 - 58 . (canceled)